EP1036067A2 - Composes pdgf inhibiteurs du recepteur de la kinase, et preparation et compositions correspondantes - Google Patents

Composes pdgf inhibiteurs du recepteur de la kinase, et preparation et compositions correspondantes

Info

Publication number
EP1036067A2
EP1036067A2 EP98960526A EP98960526A EP1036067A2 EP 1036067 A2 EP1036067 A2 EP 1036067A2 EP 98960526 A EP98960526 A EP 98960526A EP 98960526 A EP98960526 A EP 98960526A EP 1036067 A2 EP1036067 A2 EP 1036067A2
Authority
EP
European Patent Office
Prior art keywords
group
compound
slow release
åhostin
cells
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98960526A
Other languages
German (de)
English (en)
Other versions
EP1036067A4 (fr
Inventor
Alexander Levitzki
Aviv Gazit
Shmuel Banai
David S. Gertz
Gershon Golomb
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Yissum Research Development Co of Hebrew University of Jerusalem
Original Assignee
Yissum Research Development Co of Hebrew University of Jerusalem
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yissum Research Development Co of Hebrew University of Jerusalem filed Critical Yissum Research Development Co of Hebrew University of Jerusalem
Publication of EP1036067A2 publication Critical patent/EP1036067A2/fr
Publication of EP1036067A4 publication Critical patent/EP1036067A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • PDGF and its receptors participate in various physiological processes such as embryonal development and wound healing.
  • An abnormally high activity of PDGF is believed to play a central role in the etiology of certain adverse pathophysiological situations, such as atherosclerosis and restenosis [7, 8], as well as in other non-malignant diseases such as pulmonary fibrosis [9], glomerular nephritis [10], and rheumatoid arthritis [11].
  • the PDGF B- chain was acquired as the sis oncogene by the acutely transforming simmian sarcoma virus [12, 13].
  • the expression of a PDGF-like growth factor in cells infected with simian sarcoma virus or transfected with the sis oncogene leads to their transformation due to the persistent autocrine stimulation of the resident PDGF receptors.
  • Rl and R2 are each independently selected from the group consisting of alkyl, alkoxy, halogen, nitro and amine and Ar is selected from the group consisting of phenyl, ferrocene, thiophene, furane, pyrrole, indole, thiazole, imidazole and pyridine.
  • the slow release carrier is poly lactic acid.
  • the tyrphostin compound is any one or combination of the compounds described above.
  • the present invention successfully addresses the shortcomings of the presently known configurations by providing new and potent tyrphostins and delivert system for treatment of proliferative disorders.
  • FIGs. 1 and 2 present chemical formula of tyrphostin compounds according to the present invention
  • Dosing is dependent on severity and responsiveness of the condition to be treated, but will normally be a single administartion of a tyrphostin containing slow release composition, with course of treatment lasting from several days to several weeks or until a cure is effected or a diminution of disease state is achieved. Persons ordinarily skilled in the art can easily determine optimum dosages, dosing methodologies and repetition rates. In a prefered embodiment slow release application of the tyrphostins is effected as further described hereinabove and below.
  • the cell lysates were clarified by centrifugation (cooled micro fuge, 17,000 rpm, 15 min) and analyzed by SDS-PAGE (6.5 % gels) and immunoblotting with anti-phosphotyrosine antibodies (either PY 20, ICN, and subsequently a peroxidase-coupled secondary antibody, or RC20-peroxidase conjugate, Affinity, Nottingham, United Kingdom).
  • the blots were developed with a chemiluminescence detection system (Western Light, Tropix, or ECL, Amersham).
  • PDGF receptors were immunoprecipitated with PDGF-R3 or DIG-1 antibodies as described [25] prior to the analysis by immunoblotting with anti-phosphotyrosine antibodies.
  • Phosphorylation was initiated by addition of [ ⁇ - 32 P]ATP (5 ⁇ l, 3-5 ⁇ Ci; final concentration, 2 ⁇ M) and terminated after 2 min by addition of 10 ⁇ l of a solution containing 6 % SDS, 30 % ⁇ -mercaptoethanol, 40 % glycerol, and 0.5 mg/ml bromophenol blue.
  • the samples were heated for 5 min at 95 °C and subjected to polyacrylamide gel electrophoresis in the presence of 0.4 % SDS, using 10 % acrylamide gels. The gels were stained, dried and subjected to autoradiographic analysis.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pulmonology (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des composés PDGF inhibiteurs du récepteur de la kinase et faisant partie de la famille des quinoxalines, leurs procédés de synthèse et de confinement par des préparations pharmaceutiques à libération lente, ainsi que leur utilisation dans le traitement des maladies ou des affections évolutives malignes et bénignes par une application générale ou locale. Un composé élaboré selon cette invention renferme un tyrphostin représenté par la formule générale (I), dans laquelle R1 et R2 sont sélectionnés individuellement dans le groupe constitué par alkyl, alcoxy, halogène, nitro et amine, Ar étant sélectionné dans le groupe constitué par phényle, ferrocène, thiophène, furane, pyrrole, indol, thiazol, imidazol et pyridine.
EP98960526A 1997-12-01 1998-11-30 Composes pdgf inhibiteurs du recepteur de la kinase, et preparation et compositions correspondantes Withdrawn EP1036067A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/980,596 US5932580A (en) 1997-12-01 1997-12-01 PDGF receptor kinase inhibitory compounds their preparation and compositions
US980596 1997-12-01
PCT/US1998/025320 WO1999028304A2 (fr) 1997-12-01 1998-11-30 Composes pdgf inhibiteurs du recepteur de la kinase, et preparation et compositions correspondantes

Publications (2)

Publication Number Publication Date
EP1036067A2 true EP1036067A2 (fr) 2000-09-20
EP1036067A4 EP1036067A4 (fr) 2002-10-23

Family

ID=25527698

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98960526A Withdrawn EP1036067A4 (fr) 1997-12-01 1998-11-30 Composes pdgf inhibiteurs du recepteur de la kinase, et preparation et compositions correspondantes

Country Status (7)

Country Link
US (1) US5932580A (fr)
EP (1) EP1036067A4 (fr)
JP (1) JP2001524545A (fr)
AU (1) AU761030B2 (fr)
CA (1) CA2312749A1 (fr)
IL (1) IL136436A (fr)
WO (1) WO1999028304A2 (fr)

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US6329375B1 (en) 1997-08-05 2001-12-11 Sugen, Inc. Tricyclic quinoxaline derivatives as protein tyrosine kinase inhibitors
US8029561B1 (en) * 2000-05-12 2011-10-04 Cordis Corporation Drug combination useful for prevention of restenosis
US7008645B2 (en) * 1998-07-14 2006-03-07 Yissum Research Development Company Of The Hebrew University Of Jerusalem Method of inhibiting restenosis using bisphosphonates
US6984400B2 (en) * 1998-07-14 2006-01-10 Yissum Research Development Company Of The Hebrew University Of Jerusalem Method of treating restenosis using bisphosphonate nanoparticles
IL125336A0 (en) 1998-07-14 1999-03-12 Yissum Res Dev Co Compositions for inhibition and treatment of restinosis
US6358954B1 (en) * 1999-11-09 2002-03-19 Yissum Research Development Company Of The Hebrew University Of Jerusalem PDGF receptor kinase inhibitory compounds, their preparation, purification and pharmaceutical compositions including same
CA2406160A1 (fr) * 2000-04-13 2001-10-25 Hsc Research And Development Limited Partnership Nouveaux composes destines a la modulation de la proliferation cellulaire
US20020007215A1 (en) * 2000-05-19 2002-01-17 Robert Falotico Drug/drug delivery systems for the prevention and treatment of vascular disease
US8236048B2 (en) 2000-05-12 2012-08-07 Cordis Corporation Drug/drug delivery systems for the prevention and treatment of vascular disease
US6776796B2 (en) 2000-05-12 2004-08-17 Cordis Corportation Antiinflammatory drug and delivery device
US20020007213A1 (en) * 2000-05-19 2002-01-17 Robert Falotico Drug/drug delivery systems for the prevention and treatment of vascular disease
ES2275737T3 (es) 2000-09-29 2007-06-16 Cordis Corporation Dispositivos medicos revestidos.
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US9994853B2 (en) 2001-05-18 2018-06-12 Sirna Therapeutics, Inc. Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference
IL159270A0 (en) * 2001-06-14 2004-06-01 Yissum Res Dev Co Non-myeloablative tolerogenic treatment with tyrphostins
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US9181551B2 (en) 2002-02-20 2015-11-10 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US9657294B2 (en) 2002-02-20 2017-05-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
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CA2407755A1 (fr) * 2002-10-11 2004-04-11 The Hospital For Sick Children Inhibition de la secretion de facteur de croissance vegf
CN102266272B (zh) * 2002-11-27 2012-12-26 Dmi生物科学公司 一种个人护理组合物及其产品
US7608586B2 (en) * 2003-06-11 2009-10-27 The University Of Rochester Soluble low-density lipoprotein receptor related protein binds directly to Alzheimer's amyloid-beta peptide
US10517883B2 (en) 2003-06-27 2019-12-31 Zuli Holdings Ltd. Method of treating acute myocardial infarction
US20060051407A1 (en) * 2003-06-27 2006-03-09 Yoram Richter Method of treating ischemia-reperfusion injury
WO2005012234A1 (fr) * 2003-07-30 2005-02-10 The Hospital For Sick Children Composes destines a moduler la proliferation cellulaire
KR101471732B1 (ko) 2003-08-27 2014-12-16 옵쏘테크 코포레이션 안구의 혈관신생성 장애를 치료하기 위한 조합 치료법
EP1682516A2 (fr) * 2003-11-13 2006-07-26 Janssen Pharmaceutica N.V. 3-aminopyrazoles tricycliques n-substitues immobilises utilises dans l'identification de cibles biomoleculaires
JP2007530455A (ja) * 2004-03-26 2007-11-01 エイチエスシー リサーチ アンド ディベロップメント リミテッド パートナーシップ 細胞増殖を調節する化合物
US10508277B2 (en) 2004-05-24 2019-12-17 Sirna Therapeutics, Inc. Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference
US20090176725A1 (en) * 2005-08-17 2009-07-09 Sirna Therapeutics Inc. Chemically modified short interfering nucleic acid molecules that mediate rna interference
US9073997B2 (en) * 2007-02-02 2015-07-07 Vegenics Pty Limited Growth factor antagonists for organ transplant alloimmunity and arteriosclerosis
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JP2012518657A (ja) 2009-02-25 2012-08-16 オーエスアイ・ファーマシューティカルズ，エルエルシー 併用抗癌治療
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WO2010099138A2 (fr) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Procédés pour l'identification d'agents qui inhibent les cellules tumorales de type mésenchymateuses ou leur formation
US9260471B2 (en) 2010-10-29 2016-02-16 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using short interfering nucleic acids (siNA)
WO2012149014A1 (fr) 2011-04-25 2012-11-01 OSI Pharmaceuticals, LLC Utilisation de signatures de gènes de tem dans la découverte de médicaments contre le cancer, diagnostics et traitement du cancer
WO2013152252A1 (fr) 2012-04-06 2013-10-10 OSI Pharmaceuticals, LLC Polythérapie antinéoplasique
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EA202192575A1 (ru) 2019-03-21 2022-01-14 Онксео Соединения dbait в сочетании с ингибиторами киназ для лечения рака
WO2020245208A1 (fr) 2019-06-04 2020-12-10 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de cd9 en tant que biomarqueur et en tant que biocible dans la glomérulonéphrite ou la glomérulosclérose
US20220401436A1 (en) 2019-11-08 2022-12-22 INSERM (Institute National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
CN115337322B (zh) * 2021-05-13 2024-04-19 南京大学 一种rna在制备治疗肺纤维化相关疾病的产品中的应用

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CHEMICAL ABSTRACTS, vol. 090, no. 4, 1979 Columbus, Ohio, US; abstract no. 030959v, PONOMARENKO V I ET AL: "Study of the effect of substituted quinoxalines and 2-aminothiazoles on the corrosion of steel in sulfuric and hydrochloric acids" XP002154825 & VOPR. KHIM. KHIM. TEKHNOL., vol. 50, 1978, pages 3-7, *
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GAZIT A ET AL: "Tyrphostins. 5. Potent Inhibitors of Platelet-Derived Growth Factor Receptor Tyrosine Kinase: Structure-Activity Relationships in Quinoxalines, Quinolines, and Indole Tyrphostins" J. MED. CHEM., vol. 39, no. 11, 1996, pages 2170-2177, XP002072258 *
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See also references of WO9928304A2 *

Also Published As

Publication number Publication date
EP1036067A4 (fr) 2002-10-23
IL136436A0 (en) 2001-06-14
IL136436A (en) 2005-11-20
WO1999028304A3 (fr) 1999-08-12
WO1999028304A2 (fr) 1999-06-10
US5932580A (en) 1999-08-03
AU761030B2 (en) 2003-05-29
JP2001524545A (ja) 2001-12-04
AU1610899A (en) 1999-06-16
WO1999028304A9 (fr) 1999-09-16
CA2312749A1 (fr) 1999-06-10

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